1. Field of the Invention
The present invention includes novel compounds and a method of treating angiogenesis in mammals who have a need for the same which utilizes certain angiostatic .DELTA..sup.4,9(11) -steroids. These steroids are useful in treating diseases of neovascularization such as cancer, diabetes and arthritis.
2. Description of the Related Art
Angiogenesis is the development of blood vessels which typically would lead to a vascular bed capable of sustaining viable tissue. Angiogenesis is a necessary process in the establishment of embryonic tissue and development of a viable embryo. Similarly, angiogenesis is a necessary step in the establishment and development of tumor tissue as well as certain inflammatory conditions. The inhibition of angiogenesis would be useful in the control of embryogenesis, inflammatory conditions, and tumor growth, as well as numerous other conditions.
European patent application No 83870132.4 (Publication No 0 114 589) published Aug. 1, 1984 describes the use of cortisone, hydrocortisone and 11.alpha.-hydrocortisone in combination with heparin in the inhibition of angiogenesis.
The angiogensis inhibitory effects of heparin and heparin fragments in combination with cortisone is described in Science 221, 719 (1983). The use of heparin and heparin fragments in combination with hydrocortisone is set forth in the Proceedings of AACR 26, 384 (1985).
Heparin is presently used with inhibitors of angiogenesis, especially angiostatic steroids to treat diseases involving neovascularization, see Biochem. Pharmacol. 34, 905 (1985) and Annals of Surgery 206, 374 (1987). The heparin potentiates the angiogenesis-inhibiting activity of other drugs, for example of collagen biosynthesis inhibitors such as L-azetidine carboxylic acid. The problem with using heparin is that the efficacy of each preparation/batch of heparin differs due to the chemical heterogeneity of the heparin molecules.
Suramin inhibits the binding of fibroblast growth factor to its receptor during in vitro experiments. Fibroblast growth factor is one of a number of known angiogenic growth factors. See, J. Cell Physiol. 132, 143 (1987).
Suramin and 4,4'-bis[ [4-(o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazin-2-yl]amino]-2,2'stilben edisulfonic acid have been reported to possess antitumor activity. See, Gann 61, 569 (1970) and J. Clin. Oncol., 7, 499 (1989).
U.S. Pat. No. 4,599,331 discloses 20-substituted .DELTA..sup.1,4 -16-methyl steroids which did not have a .DELTA..sup.9(11) double bond which are useful as antiangiogenics when combined with heparin.
U.S. Pat. No. 4,771,042 discloses 21-hydroxy steroids which are useful in the inhibition of angiogenesis involving the co-administration of steroids with heparin or heparin fragments. The compounds of the present invention do not include --CH.sub.2 -- at C.sub.21.
International Patent Publication WO87/02672 discloses various C.sub.11 -functionalized steroids useful in the inhibition of angiogenesis when combined with heparin.
The Journal of the National Cancer Institute 81, 1346 (1989) discloses that "Suramin also appears to have antiangiogenesis activity . . . ".
The combination of suramin-type compounds and angiostatic steroids have been reported to treat angiogenesis in a warm blooded mammal, see the Journal of the National Cancer Institute 81, 1346 (1989) and U.S. patent application Ser. No. 07/483,044.
It is known that steroids alone can inhibit angiogenesis, see National Academy of Sciences USA 78, 1176 (1981) [medroxyprogesterone], Cancer Letters 43, 85 (1988) [medroxyprogesterone acetate], International Journal of cancer 35, 549 (1985) [cortisone], JNCI 74, 869 (1985) [cortisone], Cancer Research 47, 5021 (1987) [cortisone acetate] and European Journal of Cancer and Clinical Oncology 23, 93 (1987) [cortisone acetate]. The data reported in these publications is consistent with the clinicla practice of using steroids to inhibit tumors.
The angiostatic .DELTA..sup.4,9(11) -steroids (I), C.sub.21 -oxygenated steroids (II) as well as the individual compounds claimed of the present invention are usefull in treating diseases of neovascularization such as cancer, diabetes and arthritis without heparin, suramin or any other "potientator" and a method of inhibiting hair growth.
With regard to the .DELTA..sup.4,9(11) -steroids (I), in particular the compound of EXAMPLE 10 [21-bromo-6.alpha.-fluoro-17.alpha.-hydroxy-16.alpha.-methylpregna-4,9(11) -diene-3,20-dione], Swiss patent 631,999 discloses a 21-chloro-16.beta.-methyl steroid and DE 1,938,218 discloses a 21-chloro-16.alpha.-methyl steroid without a 17.alpha.-hydroxy group.
The C.sub.21 -oxygenated steroids of formula (II) are known. More specifically, the the compound of EXAMPLE 2 is known, see U.S. Pat. No. 3,291,815; the compound of EXAMPLE 3 is known, see U.S. Pat. No. 4,771,042; the compound of EXAMPLE 4 is known, see U.S. Pat. Nos. 3,980,778 (column 2, compound 3) and 4,018,918 (column 10, compound 17); the compound of EXAMPLE 6 is known, see CAS 378-61-0. The compound of EXAMPLE 7 is known, see PCT/DE85/00249 Example 1 and U.S. Pat. No. 4,975,537 where the compound is generically claimed.
The compound of EXAMPLE 14 is known, see U.S. Pat. Nos. 4,771,042 and 4,704,358. The compound of EXAMPLE 13 is known, see J. Org. Chem., 33, 1700 1968. The compounds of EXAMPLES 2-4, 8, 11 and 12 are also known.
European Patent Publication 0 268 400 (examples 6 and 62), J. Org. chem., 44, 1582 (1970), J. Med. Chem., 33, 1145 (1990), Steroids, 44(4), 3243 (1984), European Patent Publication 0 123 241 and Offenlegungsschrift DT 26 49 753 A1 all disclose 21-bromo steroids similar to those of claim 1 where R.sub.21 is --CH.sub.2 --Br.
International Publication No. WO87/01706 discloses various amino steroids but none have the same side chain identified as R.sub.21, as the .DELTA..sup.4,9(11) -steroids (I) of the present invention.
17.alpha.,21-Dihydroxypregna4,9(11)-diene-3,20-dione is known, see U.S. Pat. Nos. 3,067,193, 3,067,194 (column 29, lines 43-44), 3,158,601 (column 24, lines 52-53), 3,300,483, EP 0 156 643 and EP 0 186 948.
6.alpha.-fluoro-17.alpha.-hydroxy-16.beta.-methylpregna-4,9(11)-diene-3,20- dione 21-phosphate is known, see EP 0 221 705 (Example 13).